Known in the prior art are antianginal preparations used to arrest attacks of angina pectoris containing active substances such as glycerol trinitrate, isosorbide dinitrate, pentaerythritol tetranitrate, and others.
In addition to said active substances, these medicinal preparations contain an inert carrier which is resolved in liquid media of the body. For example, used in the prior art are granules of glycerol trinitrate containing sugar, starch, and other substances as filling materials (Soviet State Pharmacopoeia, 10th edition).
A disadvantage of the known medicinal preparations containing readily soluble substances such as sugar as a filling material, is their low stability in storage and lack of prolonged action.
Also known in the prior art are tablets of glycerol trinitrate, prepared by the microcapsulation method (Sustac Nitrong) wherein the microcapsules perform the function of the carrier material which is a derivative of cellulose such as methyl cellulose, ethyl cellulose, acetyl cellulose, cellulose acetophthalate, etc.
Medicinal preparations enclosed in microcapsules start exerting their medicinal action at delayed (to 60 minutes) terms, and this makes it impossible to use them for rapid arresting of angina pectoris attacks.
Another disadvantage of capsuled preparations is the relative complexity of their manufacture.
Known widely in the prior art are antianginal preparations manufactured in the form of tablets and dragees. These also include multi-coated pills containing synthetic polymers such as polyvinyl alcohol, and a copolymer of polyvinyl alcohol and vinyl acetate, as resolvable carrier material. Synthetic polymers are used to coat tablets or granules so that the rate of liberation of the active principle could be controlled. (French Pat. No. 2,326,933; U.S. Pat. No. 4,012,498).
Also known in the prior art are antianginal preparations in the form of chewing gum containing the active principle and various additives. The base material used in these preparations are polyacrylate polymers (U.S. Pat. No. 3,594,470).
The disadvantages of the known medicinal preparations in the form of tablets pressed with powdered synthetic polymers, and also enclosed in coats of such polymers, is that they can be improperly administered (especially by children who can chew them before swallowing) and hence produce undesirable side effects due to rapid uncontrolled absorption into the body.
The method of treating with such medicinal preparations involves the patient swallowing the medicine (peroral administration), or placing it under the tongue until it fully resolves (sublingual administration) or chewing the gum to ensure gradual administration of the medicine with saliva. In all these administration methods, the active principle penetrates the alimentary tract where it is dissolved, absorbed through the mucosa, and delivered first to the liver and then to the blood circulating system (Petkov, V., "Medicine, Body, Pharmacological Effect", Medicina i Fizkultura Sofia, 1974).
The general pharmacological disadvantage inherent in all known medicinal antianginal preparations is that when the preparations enter the alimentary tract, and later the liver, the liberated active substance is partially inactivated by the enzymatic systems in the body. The degree of inactivation of the preparations depends on specific characteristics of the living body and its physiological state which, in general, makes it impossible to dose the medicinal preparation individually so as to ensure its optimum effect.
U.S. Pat. No. 3,429,308, which issued to H.S. Russell on Feb. 25, 1969, discloses a method for administering drugs from a vehicle adhering by suction to the parabuccal cavity mucous membrane. The vehicle used to administer the drug is a gelatinous material and is configured to have a generally concave depression on its major surface and is relatively thin so as to be of a substantially flexible but resilient nature. The vehicle may also be a gelatinous material based on the alginates or a resin-based material. When a drug containing vehicle is introduced into the parabuccal cavity, it becomes adhered to the mucous membrane by virtue of a suction effect afforded by means of the concave depression. The vehicle can be in the form of a lozenge and when it is desired to administer the drug, the lozenge is merely moistened on the concave side and pressed firmly against the gum of the upper jaw of the patient. It is indicated in the patent that by firmly pressing the lozenge against the mucous membrane of the parabuccal cavity, at least some of the air is dispelled from the depression to produce a suction effect, whereby the lozenge adheres to the surface and the drug is absorbed into the mucous membrane.
Although the reference does not indicate how quickly absorption begins, it states at column 4, lines 31 et seq. that absorption is allowed to continue until the desired effect of the drug is obtained. No indication is given as to the period of time during which absorption of the drug continues.
A wide variety of drugs are disclosed which can be contained in the vehicle and include, hormones, local anesthetics, sympathomimetic amines, vasodilators, cardiovascular reactants such as glyceryl trinitrate, muscle relaxants, antihistamines, and the like.
It is indicated in this patent that the invention operates as a convenient vehicle for administering drugs which avoids known disadvantages and yet has the advantage of permitting substantially instantaneous discontinuance of administration and comprehends a vehicle for administering a drug in the form of a thin body of resilient gelatinous material having a concave depression on at least one of the major surfaces thereof and being of such shape as to enable it to be introduced into the parabuccal cavity for adherence by suction to the mucous membrane by reason of the concave depression, and wherein the material of the body is impregnated with a drug which is effective when absorbed through the mucous membrane, which drug may be of a nature such that, if administered by swallowing, it would be subject to destruction or inactivation by stomach or intestine saliva or fluid, or would cause unwanted side effects, or would require massive overdoses.
The vehicle is made by preparing a liquid solution or melt of a gelatinous material, impregnating the solution or melt with a drug, preferably of hormonal nature which is effective when absorbed through the mucous membrane of the parabuccal cavity, and forming the impregnated solution or melt into the vehicle.
The material, in main part, is a gelatine which acts as a diluent for a water soluble drug which is dissolved in the gelatine prior to the formation of the lozenge. Contrarywise, the active ingredient may be dissolved in water or other diluent and added to the lozenge by injection, soaking, spraying, dipping or any other method once the lozenge is made.
Other glyco-gelatine based mixtures, or a gelatinous material based on the alginates, or other suitable, for instance, resin-based materials may be used. However, it is indicated that a material based on gelatine is preferred.
The vehicle offers the advantage that it does not fragment so that it may be easily removed when a sufficient amount of the drug has been absorbed. Accordingly, the vehicle is particularly suitable for administering drugs which produce easily identifiable signs of sufficient absorption thereof. Since the vehicle adheres to the gum and also abuts the adjacent membrane of the lip, even to the extent of adhering to the latter, very little of the drug is washed away or inactivated by any saliva present in the patient's mouth.
As indicated above, the vehicle used in the medication is based on gelatin or its analogs (Column 3, line 23). There is no indication of other polymeric materials being used in preparing the medications. An obvious disadvantage of gelatin and its analogs when used in controlled release drugs, is the insolubility of gelatin in saliva and the impossibility of homogeneous systems with a controlled hydrophilic-hydrophobic balance predetermining the drug release rate into the mucous surfaces being developed. The medication must be removed from the mouth cavity at the end of drug action, as taught in claim 2, which makes individual and precise dosing of the drug difficult.
Another reference, U.S. Pat. No. 3,444,858 also issued to H. S. Russell on May 20, 1969, is directed to a resiliently flexible gelatinous material in the form of a strip which can be inserted into the buccal sulcus and which contains an absorbable drug. It is indicated in this patent that the invention also provides a method of making a vehicle comprising the steps of preparing a liquid solution or melt of a gelatinous material, impregnating the solution or melt with said drug and forming the impregnated solution or melt into the vehicle.
The vehicle is preferably in a form of glycol-gelatine which is sufficiently firm and solid to be resilient and is conveniently in the form of an extrusion of rectangular or oval cross section.
In a preferred form, the vehicle is impregnated with a drug of very potent nature as such drugs are usually effective even when administered in very small amounts, e.g., in doses of a fraction of a milligram.
The vehicle may be prepared by any suitable means and from any suitable flexible or gelatinous material and, in the instance wherein the material comprises mainly glycol-gelatine, various plasticizers and diluents may be incorporated, not only to improve and/or vary the qualities of the vehicle, but also to facilitate the production thereof, and the incorporation of the drug or drugs.
The strip is formed at intervals, with pairs of transverse depressions in opposite major faces thereof so as to divide the strip into a plurality of sections which are each connected to the next adjacent sections by comparatively weak ligaments.
The purpose of these ligaments is to enable the strip to be torn or otherwise divided up into individual lengths each of which consists of one or a desired number of the sections.
In this manner, the desired dosage of drug can be administered by use of an appropriate number of sections. The reference is silent as to the duration of effect or how quickly the drug is absorbed.
It is also indicated in the patent that while glycol based materials are preferred, the strips can be made from other materials. Also, as in the earlier cited Russell patent, a variety of drugs can be incorporated into the vehicles of this patent.
Solid pharmaceutical formations containing hydroxypropyl methyl cellulose are disclosed in U.S. Pat. No. 3,870,790, which issued March 11, 1975 to Hans Lowey and is assigned to Forest Laboratories, Inc. of New York, and are indicated to be useful as long-acting compositions for the administration of transmucosally absorbed therapeutic agents.
In general, the long acting carrier products of the invention are produced by combining the appropriate amount of active ingredient into the shape of troches, lozenges, tablets or suppositories with a mixture of from about 100-80% by weight of hydroxypropylmethylcellulose and from about 0-20% by weight of ethylcellulose. The produce can also contain adjuvants such as a synthetic sweetening agent and the like.
When used as a lozenge, release through the action of the saliva is continuous and the active ingredient then passes through the gastro-intestinal tract into the blood stream. However, when the composition is positioned in the buccal pouch, absorption of the active ingredient takes place through the mucosa membrane lining the pouch directly through the capillaries in the blood stream.
It is indicated in this reference that a 5 gram lozenge when held in the mouth will release its active ingredient in a regular manner over a one and one half hour period. Larger lozenges will take longer periods to release the active ingredient.
Although the reference indicates that the composition, in the form of a lozenge, can be positioned in the buccal pouch and absorption of the active ingredient takes place through the mucous membrane, there is no disclosure that the lozenge becomes affixed to the mouth mucosa and maintains its position throughout the period that the drug is released.
A pharmaceutical preparation for oral cavity administration is also disclosed in U.S. Pat. No. 4,059,686, which issued on Nov. 22, 1977 to Tanaka, et al. The preparation is characterized as being a mixture of a pharmacologically active agent, a pharmaceutical carrier and sodium polyacrylate (PANA). It is indicated in the reference that when a proper quantity of the sodium polyacrylate is incorporated in the base carrier for a preparation for oral cavity administration, the sodium polyacrylate first absorbs water and adheres strongly to the local site, then swells and dissolves gradually at the site over a long period of time, while releasing the medicinal agent substantially uniformly. It is further indicated in the reference that it has been entirely unknown that sodium polyacrylate may be used as a base for a preparation for oral cavity administration and is effective in retarding disintegration.
In this reference, the sodium polyacrylate is merely blended with the carrier which can be microcrystalline cellulose, mannitol, anhydrous lactose or other commercially available products.
It is also indicated in this patent that the PANA used can be any of those used as food additives and its molecular weight, through not critical, is preferably about 185,000 to about 8,500,000 (the intrinsic viscosity is 0.4 to 1.1 [g/dl], as measured in 2N-NaOH at 30.degree. C.). The amount to be added is 10 to 60% by weight based on total weight of the preparation.
The pharmacologically active agent suitable for administration according to the invention and intended to directly enter the systemic circulation include steroid hormones; proteins such as antiinflammatory enzymes and callicrein; peptides such as insulin, gastrins, secretin, pepstatin, and leupeptin; nitrate esters such as nitroglycerin and erythrityl tetranitrate; isoproterenol, and methacholine.
It is stated in the reference, that the pharmaceutical preparation is quite different from conventional buccal tablets and can stay in the oral cavity for 1 to 8 hours. As shown in FIG. 3 of the reference, release of Patent Blue employed in the test procedure was linear but the amount decreased with time.
It should also be noted that the sodium salt of acrylic acid is a water-soluble polymer which does not ensure a prolonged release of the drug. To achieve a minimum desired effect, the medication must contain a considerable proportion of polymer base, for which reason a small-size medication suitable for application to the mucous membrane of the mouth cavity cannot be developed. Ointments containing a sodium salt of acrylic acid as the base cannot ensure the desired accuracy of dosage, which is an essential condition for developing a medication containing a strong drug.
In U.S. Pat. No. 4,226,848, which issued Oct. 7, 1980 to Tsuneji Nagai, et al, a method and preparation for administering a medicament to the mucosa of the oral or nasal cavity is disclosed. In this reference, a water-swellable and mucose-adhesive polymeric matrix is employed which is comprised of 50 or more percent by weight of a cellulose ether and up to 50% by weight of a homo or copolymer of acrylic acid. It is indicated that the pharmaceutical preparation continuously releases the medicament at a controlled rate and causes the released medicament to be absorbed through the mucosa. It is indicated in the reference that a wide variety of medicaments can be employed in the preparation including an algesic and anti-inflammatory agents, antihistamines, topical anesthetics, vasodilators, oral antiseptics, drugs for the digestive organs, and a variety of other drugs including hypotensives, sedatives, anti-tumor agents and antacids.
When the cellulose ether and polyacrylic acid or its pharmaceutically acceptable salt are used singly in producing a pharmaceutical preparation, the resulting preparation is unsuitable as a slow-releasing preparation because it does not adhere to the mucosa of the oral or nasal cavity or even when it adheres, it is relatively rapidly disintegrated, dispersed or dissolved by the saliva or other secretions. In contrast, the pharmaceutical preparation of the reference containing a mixture of these in a specified ratio has sufficient adhesion to the mucosa, and does not dissolve, flow out and get out of shape although it is swollen and softened with the saliva or secretions. Moreover, the preparation, in accordance with the reference, does not irritate the mucosa of the oral or nasal cavity and releases the medicament uniformly over a long period of time either topically or through the entire body.
The specified ratio of the two polymers which form the polymeric matrix is indicated to be essential in order for the slow-releasing preparation of the reference not to cause whitening or blisters of the mucosa of the oral or nasal cavity, and also to release the medicament at a controlled rate.
When the amount of the acrylic acid polymer or its pharmaceutically acceptable salt is more than about 50% by weight, the pharmaceutical preparation irritates the mucosa of the oral or nasal cavity, and tends to cause marked whitening of the mucosa and the marked occurrence of blisters therein.
Preferably, the polymeric matrix used in the reference consists of about 65 to about 90% by weight of the cellulose ether and about 35 to about 10% by weight of the polyacrylic acid or its pharmaceutically acceptable salt.
The cellulose ether used in the reference is a cellulose derivative resulting from the partial or whole etherification of a plurality of hydroxyl groups of cellulose, and includes, for example, lower alkyl ethers, hydroxy lower alkyl ethers, and carboxy lower alkyl ethers of cellulose. It is also stated in this patent that the rate of releasing the medicament can be controlled easily to suit the purpose of therapy by changing the ratio between the cellulose ether and the acrylic homo- or copolymer or its pharmacetically acceptable salt, within the specified range.
Additionally, at column 7, lines 55 et seq. of the reference, it is indicated that the preparation of the invention swells upon absorption of saliva and gradually releases the medicament at a controlled rate. There is no indication that the medicament is absorbed immediately and at a uniform rate.
Although the preparation is capable of swelling and adhering to the mucous surfaces of the mouth and nose, it does not dissolve in saliva or secretions (column 8, lines 9-17). At the end of its action, the medication is removed from the mouth or nose cavity. The method and compositions are characterized by disadvantages in that the preparation is insoluble, the duration of the effect of the medication is difficult to determine, and the preparation is inconvenient to use because it requires removal by the patient. Moreover, the medications according to this Pat. No. 4,226,848, are dispersions, for which reason they are relatively nonuniform and may affect uniform drug release.
A sustained release therapeutic composition is disclosed in U.S. Pat. No. 4,226,849, filed June 14, 1979, subsequent to the effective filing date of the present invention, which issued to J. M. Schor and is also assigned to Forest Laboratories, Inc. of New York. In this patent, it was reported that a significantly greater control of the release pattern is achieved by a chemical modification which results in an increase in carboxyl functionality in the hydroxypropylmethylcellulose molecule. Although the actual mechanism is not known, it was speculated that the slower release rate arises from a decreased rate of swelling or a lower water solubility resulting from a hydrogen-bonding interaction between the carboxyl and the carbonyl and/or hydroxyl groups in the hydroxypropylmethylcellulose which has been subjected to both hydrolysis and oxidation.
In contrast to the disclosure of U.S. Pat. No. 3,870,790, the earlier Forest Laboratories, Inc. patent, it is indicated by the patentee that moisture contents as low as 0.5% can be present during the preparation of tablets and other compressed solid shapes. The amount of moisture present influences the amount of pressure necessary to prepare the shaped objects and the integrity thereof, but plays a minor role as compared to the chemical structure in the rate or release of medicaments from the chemically modified hydroxypropylmethylcellulose. Similarly, while the release pattern is governed at least in part by the size of the tablet or other shaped object as well as by the degree of compression, the chemical structure of the hydroxypropylmethylcellulose which has been subjected to chemical modification superimposes its effect and is the dominant factor in the control of the release rate.
Drugs embedded in the "Synchron" Carrier System, as the patentee terms the carrier base, are intended to attain and maintain a steady concentration of drug in blood or tissues. One objective in using these preparations is to reduce the dosage frequency, to make therapy simple and convenient, and to improve compliance by the patient. In addition, by maintaining a reasonably constant plasma concentration of drug, excessive or premature peaking is avoided and side effects, which may be associated with peak concentrations of drug, would be lessened. In addition, a more uniform concentration of drug in blood and tissues is much more likely to be paralleled by a more uniform pharmacologic effect and response. With dissolution being the main rate-limiting step in drug absorption, the rate of solution of the drug from the dosage form into the surrounding fluids at the absorption site is controlled by the chemical changes induced during production of the "Synchron" Carrier System. The drug can further be released to a specific site at a uniform rate independently of the pH environment, resulting in steady concentrations of the drug in tissues. Drugs incorporated into the "Synchron" Carrier System vehicle are prone to be absorbed completely, but more slowly, and are formulated to maintain the therapeutic effective level of the particular drug and to produce a prolonged response and a diminished rate of unassimilated drug elimination.
In an article by Ishida et al., Chemical and Pharmaceutical Bulletin, 29(3) 810-816, March 1981, entitled "New Mucosal Dosage Form of Insulin" attempts to prepare a new oral mucosal dosage form of insulin with a view to solving problems encountered by injections were reviewed. The oral mucosal dosage form of insulin consisted of the core-base which contains cacao butter, insulin and an additive, and the peripheral-base which contained a mixture of hydroxypropyl cellulose-H (HPC) and Carbopol-934 (CP). The suitable mixing ration of HPC and CP in the peripheral-base was chosen as 1:2 on the basis of experimental results concerning the stickiness, dissolution properties, viscosity and fracture resistance. This dosage form could stick tightly to the oral mucosa of beagle dogs for 6 hours.
In a preliminary experiment, a compressed disc which consisted of HPC, CP and insulin was applied to the oral mucosa in beagle dogs. No absorption of insulin was found possibly for the following two reasons: (1) Only a very small amount of insulin reached the membrane because insulin was released in all directions and the part released into saliva was swallowed and inactivated, (2) HPC and CP seemed to be unsuitable as the base materials for mucosal absorption of insulin.
In order to find a suitable mixing ratio of HPC and CP for use as the peripheral base, the stickiness to the mucosal membrane, dissolution properties, viscosity of the solution and fracture resistance, were investigated. No clear relationship was found between the mixing ratio of HPC and CP and the stickiness to the mucosal membrane, suggesting that the stickiness was related to the content of moisture on the membrane. The tablet did not stick to a very moist membrane but stuck tightly to one with little moisture. If the moisture level was satisfactory, however, a tablet containing more CP usually stuck more tightly to the mucosal membrane for a longer time period. Thus, in order to affix this tablet to the oral mucosa, it is necessary to wipe away the saliva with absorbent cotton.
Product information reports were available in September, 1981 and January, 1982 from Merrell Dow Pharmaceuticals, Inc. on transmucosal tablets marketed under the name "Susadrin". Reference is made in these reports to the "Synchron System" mentioned in the above cited Lowey and Schor patents both of which are assigned to Forest Laboratories, Inc. The first report dated September 1981, "Susadrin.TM. (nitroglycerin), transmucal tablets--Product Information and Clinical Summary--Merrell Dow" was 8 pages in length and indicated that Susadrin tablets have demonstrated activity at, the earliest period measured, 3 minutes after placement in the buccal pouch and a duration of activity of up to 6 hours.
Another Merrell Dow report entitled "How to Benefit most from Susadrin.TM. (nitroglycerin) Transmucosal Tablets", an 8 page brochure, provides directions to a patient for whom Susadrin tablets have been prescribed. The report states that:
"Susadrin Transmucosal Tablets are a unique clinically proven way to deliver nitroglycerin to your system. Rather than placing it under your tongue (like a sublingual tablet) or swallowing it, you place Susadrin between the upper lip and gum or in the buccal pouch. Within minutes, it will adhere comfortably and begin releasing medication. It will continue to release medication until it dissolves. In some cases, the tablet isn't completely gone even after five hours."
"After the Susadrin Tablet is in place for a minute or two, it will adhere comfortably to the oral mucosa. From then on, the tablet is not easily dislodged, and you may talk, eat, and drink quite normally while the tablet is in place. You will also find that a properly placed tablet is not noticeable to others.
The average dissolution time for a Susadrin Transumcosal Tablet is three to five hours, but the rate at which Susadrin Transmucosal Tablets dissolve in your mouth can depend upon you. For example, touching the tablet with your tongue or drinking hot liquids, tends to increase the rate at which the tablet dissolves."
A third report by Merrell Dow is entitled "Transmucosal Nitroglycerin (Susadrin.TM.) in the treatment of Angina Pectoris". Report number 1 is a 7 page discussion of Susadrin and indicates that Susadrin tablets represent a new nitrate delivery system that provides rapid onset, activity at three minutes--and prolonged duration of action--up to 5 hours of angina prophylaxis. The report is mainly concerned with the results obtained by five leading investigations and indicates that to the date of the report, the results of 50 patients have been received.
In an article by S. S. Davis, et al entitled "Cintigraphic Studies in the In Vivo Dissolution of a Buccal Tablet", which was published in Modern Concepts in Nitrate Delivery Systems, Royal Society of Medicine, International Congress and Symposium Series No. 54, Pgs. 30-37, 1983, it was disclosed that the therapeutic efficacy of drugs with short biological half lives can be improved by the use of sustained-release formulations that provide a slow and controlled input of drug to the systemic circulation. In the experimental work reported in this reference, sustained-release dosage forms of glyceryl trinitrate were employed in tablets, ointments and adhesive patches. Buccal tablets were evaluated wherein the drug was entrapped in a slow eroding non-disintegrating tablet base or matrix such a s hydroxypropylmethyl cellulose.
The buccal tablet employed resembled a conventional tablet, but in this type of formulation, the drug was entrapped in a slowly eroding non-disintegrating tablet base or matrix. Modified hydroxypropylmethylcellulose of the type disclosed in the Forest Laboratories, Inc. U.S. Pat. No. 4,226,849 discussed above, was indicated to be a suitable matrix material. On contact with water, the hydroxypropylmethylcellulose forms a gel-like layer and it is thought that the release of the drug contained in the matrix is controlled by diffusion of the drug through the gel layer and erosion of the gel itself.
Although hydroxypropylmethylcellulose used in the above-described medications prolongs the effect of nitroglycerin, the prolongation is insufficient because of its high hydrophilicity. For this reason, hydroxypropylmethylcellulose cannot be used as a basis for manufacturing a medicinal film similar to ocular medicinal films. Moreover, a sufficient prolonged effect is only achieved at a high proportion of the methylcellulose. In this connection, buccal tablets having a considerable weight (132 mg) are normally employed. Application of these tablets to the mucosa of the mouth cavity is therefore inconvenient for the patient. Additionally, hydroxypropylmethylcellulose has a low adhesive capacity relative to the mouth mucosa.
The reference further states that the in vitro release characteristics of a matrix system can be measured using a standardized dissolution test. However, the behavior in vivo is more difficult to assess; a possible approach would be the repeated administration of buccal tablets to the same volunteers and assaying individual tablets after different contact times. This approach would be extremely tedious to undertake and a more satisfactory alternative was proposed which involved the use of external scintigraphy to monitor the release of a gamma emitting radionuclide. However, practical considerations prevented the labelling of the drug directly and, therefore, a technetium-99m-labelled diethylenetriamine pentaacetic acid was used as a model.
It was stated in this reference to Davis et al. that four volunteers placed the tablets on separate occasions in the upper buccal cavity, the lower buccal cavity, or behind the lower front incisors. The release rate from the tablets placed behind the lower front incisors was much faster than for the tablets placed in the buccal cavities. For two of the four volunteers, there was no difference in release rate for upper and lower cavities but for the others, the release rates were very different (Table A).
TABLE A ______________________________________ The effect of position on the release of .sup.99m Tc- DTPA from a sustained-release buccal tablet Percentage released in 2 h Lower front Lower Upper Subject incisors buccal buccal ______________________________________ AH 71 17 19 RK 96 18 15 MS 95 22 70 PP 94 13 65 ______________________________________
To determine the effect of chewing and drinking, two subjects placed the sustained release tablet in the lower buccal cavity and then at predetermined times, performed a set pattern of chewing and drinking. The release pattern of the .sup.99m Tc-DTPA was not changed to any marked extent.
It was concluded in this article that the buccal sustained release system based upon a hydroxypropylmethylcellulose matrix (Synchron) provided a slow release of entrapped materials. It was therefore a suitable material for the administration of glyceryl trinitrate.
The release patterns from tablets placed in the lower buccal cavity show greater inter-subject variation than was observed within individuals. The position of the tablet (upper or lower buccal cavity) could be important in some individuals. However, a consistent pattern of release should be obtained in the same individual, so that a given patient could be titrated to a given regimen. Eating and drinking appear to have little effect on release rates.
In another article by S. S. Davis et al. entitled "Design and Evaluation of Sustained Release Formulation for Oral and Buccal Administration" Adv. Pharmacother. Vol 1, pp 17-25 (Karger, Basel 1982), the Synchron controlled release system was discussed. In this article, radio--labelled tablets were employed and the subjects receiving the tablets were seated against the face of a gamma camera. Each subject received a rapidly dissolving tablet which was placed in the lower buccal cavity, followed on a second occasion by the sustained release buccal tablet--the rapidly dissolving tablet had dissolved completely after 20 minutes while the sustained release Synchron formulations was still releasing the marker after 3 hours. This article concluded with a discussion wherein Dr. Davis was asked whether he ever experienced a patient that could dissolve the buccal tablets within 10 minutes. In reply Dr. Davis stated:
"We found, with volunteers who had dry mouths, that we got a very slow release. But in no occasion did we find a very rapid release with these formulations. 10 minutes sounds very quick for the Synchron system. A much slower release than that would be expected. I have a feeling that the volunteer or patient was doing something unusual with the tablet. For example, moving it around the mouth, rather than letting it remain stationary in the buccal cavity."
In a further study involving the evaluation of the Synchron system; P. B. Daly et al. authored an article entitled "Scintigraphic assessment of the in vivo dissolution rate of a sustained release tablet", International Journal of Pharmaceutics, 10 (1982) 17-24. It is stated that with respect to slow release systems, the basic process of release from a matrix is leaching of the medicament by the surrounding fluid which is able to permeate into the matrix through pores and interparticulate spaces. The drug dissolves into this fluid phase and diffuses from the system via capillary channels. In the case of `Synchron`, the surface of the tablet swells to a gel-like consistency following drug release by a combination of diffusion and surface erosion.
Additionally, the "Synchron" system does not provide satisfactory results because of its physico-chemical properties, since when it is used, the prolongation effect is achieved due to the presence of a large amount of hydroxypropylmethylcellulose. Thus, the weight of the Susadrin buccal tablets is quite large (132 mg). The application of such tablets to the mouth mucosa is not convenient for the patients. Such tablets do not have high adhesion to the mouth mucosa. In contrast, applicants antianginal film is in the form of thin plates with high adhesive qualities for the mouth mucosa. As hereinafter indicated in the examples, a comparative study of the effect of nitroglycerin, Trinitrolong.RTM. (applicants' films) and Susadrin is set forth. It has been demonstrated that the arresting effect of Susadrin tablets, given to 8 patients with typical angina pectoris of effort, which was successfully reproduced under the load on a treadmill, was registered in only one patient, as long as nitroglycerin tablets were sublingually provided for arresting effect in 6, and Trinitrolong--in 5 patients, suffering angina pectoris (the tablets were given to the patients under the conditions of continued physical load after the beginning of the attack). Consequently, the arresting effect of applicants' antianginal plate was equal to the effect of ordinary nitroglycerin tablets taken sublingually, and the arresting effect of Susadrin was noted in only one of the eight patients.
In an article published in the USSR entitled "Trinitrolong.RTM.--A New Nitroglycerin Drug with Prolonged Effect" by V. I. Metelitsa, et al, Terapevticheskiy Arkhiv. 52/5, 54-59 (1980), clinico-pharmacological studies of Trinitrolong.RTM., also referred to as TNL, were made of forty-three patients with ischemic heart disease. As reported in the reference, acute pharmacodynamic studies, as well as the study of efficacy, were conducted in comparison with the effect of well known nitroglycerin drugs. The results of comparison of the pharmacodynamic effect of Trinitrolong used in the form of a plate for application of the gums and nitroglycerin in the form of tablets for sub-lingual use were presented. When using Trinitrolong, the hemodynamic effects were observed in the first one-two minutes after application of the plate, and lasted on the average for three to four hours. According to the data, repeated individual selected standard physical loads with the treadmill in combination with EKG monitoring, the ST segment had a stable uniform depression before drug administration. The effect of the drug, according to the changes of the value of ST segment depression after drug administration, was shown to differ from the dynamics of the effect of a placebo that is, the natural dynamics of the shift of the ST segment in the patients with ischemic heart disease during loads.
The long term use of Trinitrolong in nine patients with ischemic heart disease confirmed the effectiveness of the drug in relation both to the decreased average frequency of attacks of angina pectoris and the number of tablets of nitroglycerin used during the attacks, as well as the average volume of work done during testing on a bicycle ergometer. The best effect was noted when using the Trinitrolong in the form of plates affixed to the gums. It was concluded in the above mentioned Metelitsa et al. publication that the use of Trinitrolong in the form of a plate on the mucous membrane makes it possible to quickly arrest attacks of angina pectoris and at the same time, to uniformly prolong the effect of nitroglycerin for three to four hours and more. It was also indicated that the method of individual dosage of Trinitrolong made it possible to improve the efficacy of treatment when taking minimum doses or less of nitroglycerin and at the same time, to avoid side effects which sometimes occur after taking nitroglycerin. In another article by S. Yu. Martsevich and V. I. Metelitsa entitled "Comparison of the Effect of Trinitrolong Plates and Nitroglycerin Tablets in Arresting Attacks of Stress Angina Pectoris", Terapevticheskiy Arkhiv. 53(4); 16-18(1981), there is described a study of nine ischemic heart disease patients with typical stress angina pectoris. These patients frequently had pain of considerable intensity and fast acting medicinal agents were required.
Nitroglycerine tablets taken sublingually have been successfully used to this end for 100 years. However, the duration of action of the latter is not over 20-30 min. Therefore, it does not always protect patients from repeated angina pectoris attacks. Prolonged action nitroglycerine preparations recently developed (Sustac, Nitrong, and the like) do not provide a rapid effect. Therefore, they cannot be used to arrest angina pectoris attacks. The new long acting preparation Trinitrolong.RTM. (TNL) combines the properties of nitroglycerine for sublingual use and prolonged nitrates, and it is intended for both long term prophylaxis of angina pectoris attacks and for their rapid arrest.
In this comparison, all patients underwent continuously increasing graduated work loads on the bicycle ergometer by the standard protocol.
On the test day, the patients underwent 3 bicycle ergometer work periods at least 4 hour intervals. The patients developed a typical angina pectoris attack during each work period. The first work period was the control. When the second work period ended, the patients were given 0.5 mg nitroglycerine sublingually. Upon stopping the third, a TNL plate, which contained 2 mg nitroglycerine, was applied to the front of the upper gums above the teeth or in small incisions. The duration of the angina pectoris attacks was recorded by stopwatch. The EKG (leads V.sub.3 -V.sub.6) and arterial pressure were recorded at the end of each minute of working and rest.
It was indicated that the preparations were effective to the same degree in arresting a stress angina pectoris attack. Both the sublingual use of the tablet and application of TNL to the mucosa of the upper gum equally rapidly removed pain and eliminated indications of myocardial ischemia on the EKG.
While arresting an angina pectoris attack, TNL retains its prophylactic effect for 3-4 hours and longer. A combination of the capacity of TNL to rapidly reduce an angina pectoris attack and have a prolonged prophylactic antianginal effect makes the preparation particularly valuable in the treatment of patients with frequent angina pectoris attacks of effort and at rest.
A further article by Savvateev et al. "THE PHAPMACODYNAMICS OF TRINITROLONG AND SUSTAC ACCORDING TO THE DATA OF TESTING WITH PHYSICAL LOAD", Terapevticheskiy Arkhiv, 53(1); 49-53(1981) discloses a study of the special features of pharmacodynamics of preparations of nitroglycerin with prolonged effect, in particular the new drug Trinitrolong (TNL) in the form of a plate containing 2 mg of nitroglycerin for application to the mucous membranes of the mouth and in the form of capsules for internal administration. The effect of Sustac containing 6.4 mg of nitroglycerin was also studied.
The study was made on 21 males suffering from IHD; their ages ranged from 38 to 63 (the average age was 51.+-.6 years). The duration of the illness varied from 1/2 a year to 12 years (on the average 2.7 years). All of the patients suffered a typical stable angina pectoris of effort with frequency of attacks from 1 to 12 in 24 hours. In 9 patients, there have been myocardium infarcts in the past documented by the presence of a pathological wave Q on the EKG at rest. Coronaroangiography was conducted on 7 of the patients (L. S. Matveyeva and V. P. Mazayev) which confirmed the presence of an atherosclerotic stenosing process with a decrease in the main branches of the coronary arteries for more than 75% of their lumen. In 8 of the patients, the EKG at rest was characterized by symptoms of scar damage to the myocardium; the other 13 patients were normal. At the same time, in all of the patients during bicycle ergometry test on the EKG, one could observe undoubted symptoms of myocardium ischemia in the form of horizontal or downsloping depression of the ST segment by 1.5 mm and more which, in all cases, was accompanied by angina pectoris stress. The threshold value of the double product (DP) after application of TNL amounted to 235.9.+-.15.9 and for the control test--175.0.+-.8.6 (p 0.001). Then the decrease of the depression of the ST segment after application of TNL amounted to 1.60.+-.0.15 mm that is during the control test was less than--1.90.+-.0.16 mm (p 0.05). Four patients who had a background of taking TNL showed a marked increase in tolerance to work; it was necessary to stop the test due to general fatigue without having achieved the criteria for stopping the test that is without ST segment depression and/or angina pectoris attack. Other drugs did not show such a marked increase in tolerance and difference in the decrease of the depression of the ST segment; in comparison with the control test they proved it to be not so perceptible. Moreover, the DP (DP is maximal heart rate x systolic blood pressure) for each patient was calculated after giving Sustac and TNL for application on the gums at a fixed point in the load that is, at an intermediate point corresponding to the maximum volume of work completed on the bicycle ergometry in the control tests. At this same work level, the value of the DP after taking the nitroglycerin drugs was smaller than the control. The difference was significant for TNL (p 0.05). At this same fixed point of the work load, the degree of decrease of the depression of ST segment was proven to be smaller (p 0.01) for all nitroglycerin drugs in comparison with the control. In this article, it was concluded that Trinitrolong, a new nitroglycerin drug with a prolonged effect in the form of a plate for application on the mucous membranes of the upper gum, and to a lesser degree, Sustac and medicinal film in capsules per os, cause an increase in tolerance to work load with a bicycle ergometry test in patients with ischemic heart disease verified in comparison with a placebo.
A 15 page brochure by Davidov, Khromov, Metelitsa, Sarycheva and Babajan entitled "Trinitrolong", published by the Ministry of Public Health of the U.S.S.R. also presented a review and evaluation of the use of Trinitrolong for the treatment of cardiovascular diseases. It is indicated in this article that due to its hydrophilic nature, the thin oval plates containing the Trinitrolong stick easily to the mucous membrane and gradually release nitroglycerin. Immediately after the application of the plate, their required therapeutic effect is observed that lasts from two to four hours or more. The steady nitroglycerin release, as well as the optimal dosage adopted to the individual requirements of the patient, decreases side effects considerably. In patients administered 0.5 mg. pills of sublingual nitroglycerin, peripheral hemodynamic effects were observed within one minute, and the optimum effect was reached within five minutes. However, after thirty minutes, the effect of the pill had disappeared. In application of a two milligram Trinitrolong plate to the gum of the same patients, peripheral and central hemodynamic effects were observed within one minute, and the optimum effect was reached within thirty minutes and lasted on the average for three hours, depending on the individual ability to dissolve the polymeric membrane. During physical exercise and after application of Trinitrolong to the mucous membrane of the oral cavity, patients demonstrated a decrease in the ST-segment depression to its complete normalization.
In U.S.S.R. Inventors' Certificate No. 810,241, assigned to the same assignee as the present invention and published March 7, 1981 by the same inventors of this application, a method is claimed for individual dosaging of film forms of medicinal agents employing an absorbable polymeric carrier film which can be attached to the buccal mucous membrane. Illustrative of the film, which is a resorptive polymeric carrier film, are polymers and copolymers of polyacrylic acids. It is indicated in the Inventors' Certificate that according to the invention, it is possible to maintain a continuous pharmacodynamic effect which is more uniform than that obtained by previously known methods.
A film-carrier was secured onto the mouth mucous membrane without a medicated compound in order to determine its resorption time and, hence, possible time of penetration of the medicated compound into the body. Then a film was selected with a content of the medicated compound which would be sufficient to penetrate into the body during the established period of the film resorption. Thereafter the film with the medicated compound was bonded one or more times on various areas of the mouth mucous membrane. The glued film became resorbed whereby the medicated compound was permanently resorbed directly by the mouth mucous membrane. In this manner it passed into the systemic blood circulation avoiding the liver. This ensures prevention of the medicated compound from decomposition by liver enzymes or contents of the gastroenteric tract. During the entire period up to a complete dissolution of the film (several hours) the therapeutic concentration of the medicated compound in the blood was retained and the required permanent pharmacodynamic effect ensured.
In the first example of the Inventor's Certificate a film-carrier without a medicated compound weighing 13 mg was bonded to the mouth mucous membrane of a volunteer in the region of the upper gingiva over the premolar tooth. After 1.5 hours the film was fully resorbed. On the basis of the available data on pharmacokinetics of nitroglycerin, to maintain a constant therapeutical concentration of the preparation in the blood, it was indicated that 0.5 mg of nitroglycerin should be administered every half an hour. Consequently, 1.5 mg of nitroglycerin should be administered to the given patient over 1.5 hours. The film corresponding to the established dose i.e. 1.5 mg, is selected from a series of polymeric films with different contents of nitroglycerin. The selected film with a mass of 15 mg consisting of a base (a copolymer of acrylamide, vinylpyrrolidone and ethylacrylate) and nitroglycerin contained in an amount of 10 to 30% by mass of the film or plate was fixed to the mucous membrane of the top jaw gingiva. The time of occurrence, duration and level of the effect were evaluated by the method of tetrapolar impedance plethysmography from a limb through the variation of the amplitude of waves "a" and "b" before and after administration, of a film with nitroglycerin with the data before and after sublingual administration of a granule of nitroglycerin. Analysis of the curves showed that the method according to the Inventor's Certificate made it possible to obtain a pharmacodynamic effect within several minutes in both instances. However, in the sublingual method this effect gradually diminished and stopped after 20-30 minutes, whereas the method disclosed in the Inventor's Certificate made it possible to maintain a continuous pharmacodynamic effect for 1.5 hours and longer, i.e. several times longer and more uniform than by sublingual administration. In a second example, the film-carrier without the medicated compound as described was applied to the mucous membrane of the jaw gingiva of a patient. The film was fully resorbed after 110 minutes. Thereafter, on the basis of the pharmacokinetics of nitroglycerin, the patient should be administered the medicated compound in a dose of 2 mg over 2 hours to maintain a permanent therapeutic concentration of the preparation. The film corresponding to the established dose, i.e. 2 mg, was selected from a series of polymeric films with different contents of nitroglycerine. The selected film weighing 15 mg and consisting of a base (copolymer) and nitroglycerin in the dose of 2 mg was fixed to the mucous membrane of the upper jaw gingiva. The evaluation of the pharmacodynamic effect was performed by the method of tetrapolar impedance plethysmography of a finger of the patient before and after the administration, of the film with nitroglycerin in comparison with the data before and after the sublingual administration of a granule of nitroglycerin (0.5 mg). Analysis of the data shows that the method of application of the medicated compound with the individually selected dosage made it possible to obtain the pharmacodynamic effect within 2 minutes and this effect lasted uniformly for 110 minutes. The return to the initial state was recorded by the end of the second hour from the moment of administration of the preparation.
In a third example in the Inventor's Certificate, a film-carrier without the medicated compound weighing 25 mg was fixed onto the mouth mucous membrane in the area of upper gingiva of a patient. The polymeric film was bonded after 30 seconds due to its swelling upon contact with saliva. The film was fully resorbed within 4 hours 45 minutes. Therefore, on the basis of the data on pharmacokinetics of nitroglycerin, 4.5-5 mg of nitroglycerin should be administered to this patient within 4.5-5 hours. A film with the content of 5 mg of nitroglycerin was selected and fixed to the mucous membrane of the mouth cavity in the region of the upper gingiva. Analysis of the obtained data showed that in the patient the polymeric film was resorbed over a period 3 times longer than in the first example and to ensure the permanent pharmacodynamic effect during this time the film should be used with the polymeric carrier containing the triple dose of nitroglycerin. However, such a dose would have caused undesirable side effects in the patient of the first example.
Finally, a film-carrier without preparation according to the first example and weighing 25 mg was fixed to the upper gingiva mucous membrane of a patient. The film was bonded to the mucous membrane within 1-2 seconds. The film was fully resorbed after 38 minutes. Therefore, during this period the patient should not be given more than 0.5-1 mg of nitroglycerin. The film with 1 mg of nitroglycerin was selected and bonded to the mouth mucous membrane. Analysis of the data showed that the polymer film in the patient was resorbed about 8 times more rapidly than in the patient of the third example. Consequently, the administration of a dose 8 times lower than that of the third example made it possible to maintain the therapeutic effect within the established period of time without any undesirable side effects.
In U.S.S.R. Inventors' Certificate No. 806,037, also assigned to the same assignee as the present invention and published Feb. 23, 1981 by the same inventors of this application, there is disclosed an antianginal preparation, which has prolonged action and reduced side effects. The antianginal preparation contains a water soluble carrier homopolymer of acrylamide, n-vinylpyrrolidone or their copolymers with acrylates. It is indicated in the Inventors' Certificate that the preparation can also contain dispersions of solid fats with melting points of 30.degree. to 50.degree. C. in order to insure a prolonged effect.
In USSR Inventor's Certificate No. 387,559, also assigned to same assignees and which corresponds to U.S. Pat. No. 3,935,303, there is disclosed polymer-base ocular medicinal films which are relevant to the antianginal film of the present invention. The ocular medicinal films are not suitable, however, in that they are only based on water-soluble polymers which, according to the inventors, dissolve completely in lachrymal fluids within 30 to 40 minutes. Unlike the conjunctival cavity, where polymer solutions are retained for a considerable time, polymer solutions resulting from dissolution of such films in the mouth cavity disappear relatively rapidly. Therefore, films dissolving within a relatively short time do not ensure the required prolonged effect, i.e., a few hours, when used as nitrate-containing medications applied to the mucosa of the mouth cavity.
The main object of this invention is to provide a novel medicinal form, viz., a medicinal plate having antianginal action, characterized by prolonged action, improved accuracy of dosage of the active substance which is soluble in saliva and stable in storage.
The specific object of the invention is to provide a novel medicinal form, namely, an antianginal plate which can be used as a medicinal preparation characterized by prolonged action, increased accuracy of dosage of the active principle, and stability in storage.